Abstract 2973: Rac inhibitors for cancer therapy
Authors: Grace Enid Velez Crespo, Eliud Hernandez, Suranganie Dharmawardhane, Cornelis Vlaar, Linnette Castillo, Lilia Kucheryavykh
Journal: Cancer Research (2022)

Abstract Among all cancers worldwide, breast cancer is the first cause of death in women. One of the most aggressive subtypes of breast cancer is the triple negative form, which account for the 10-15% of breast cancer cases. Due to its complex heterogeneity triple negative breast cancer available treatments are limited, being chemotherapy in the first line of use. Despite advances in the search for new treatments, there is still a lack of effective therapies, being the metastatic disease the principal cause of breast cancer mortality. Therefore, it is critical to develop a new and effective strategies to inhibit metastasis. The Rho GTPase Rac has been identified as a promising target for anti-metastatic cancer therapy as it has been shown to play key roles in metastatic cancer cells dynamics as: cellular adhesion, migration, proliferation, survival and invasion. To this extent, in an effort to find a compound with increased Rac inhibitory capacity our group developed Ehop-016 derivatives HV-107 and HV-118. Previously we have reported HV-107 and HV-118 to affect cell viability promoting a G2-M cell cycle arrest with a sub-G1 population indicative of cell death in MDA-MB-231. Also, an increase of caspases activity validating apoptosis as a mechanism of cell death was shown. In addition, a decrease in tumor growth and metastasis by ~35 to 40% in an in vivo study using HV-118 at 1 mg/kg body weightwas also reported. Currently, through pulldown assays we have showed HV-107 and HV-118 to inhibit Rac activity at~500-2000 nM and 10 nM respectively in MDA-MB-231 and MDA-MB-468 breast cancer cells. Using trypan blue excision assay HV-107(&amp;gt;500 nM) and HV-118(&amp;gt;50 nM) were shown to affect cell viability promoting a G2-M cell cycle arrest in MDA-MB-468. We also demonstrated HV-107 and HV-118 to inhibit the direct downstream effector of Rac, PAK at &amp;gt;500 nM(HV-107) and &amp;gt;50 nM(HV-118) in MDA-MB-231 cells. In addition, HV-107 was also shown to increase Rho activity at concentrations significantly higher than the effective for Rac inhibition. Rho activity up-regulation has been reported to negatively affect migration of cancerous cells. Finally, we tested HV-107 in a mouse model of metastatic breast cancer. A decrease of ~ 40% in liver metastasis was shown for mice treated with 5 mg/kg BW HV-107. Taken together, our results indicate HV-107 and HV-118 are approximately 4-100 times more efficient than the parent compound Ehop-016 and have potential as anti-breast cancer metastasis therapeutics. This study is supported by NIH Grant 1SC1GM122691, and PRINBRE P20GM103475 from NIGMS of the NIH to GVC Citation Format: Grace Enid Velez Crespo, Eliud Hernandez, Suranganie Dharmawardhane, Cornelis Vlaar, Linnette Castillo, Lilia Kucheryavykh. Rac inhibitors for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2973.